Trauma to the brain or spinal cord caused by physical forces acting on the skull or spinal column, by ischemic stroke, arrested breathing, cardiac arrest, Reye's syndrome, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, encephalomyelitis, hydrocephalus, post-operative brain injury, cerebral infections, various concussions and elevated intracranial pressure results in edema and swelling of the affected tissues. This is followed by ischemia, hypoxia, necrosis, temporary or permanent brain and/or spinal cord injury and may result in death. The tissue mainly affected are classified as grey matter, more specifically astroglial cells. The specific therapy currently used for the treatment of the medical problems described include various kinds of diuretics (particularly osmotic diuretics), steroids (such as, 6-.alpha.-methylprednisolone succinate) and barbiturates. The usefulness of these agents is questionable and they are associated with a variety of untoward complications and side effects. Thus, the compounds of this invention comprise a novel and specific treatment of medical problems where no specific therapy is available.
Two recent publications, one entitled "Agents for the Treatment of Brain Injury" 1. (Aryloxy)alkanoic Acids, by Cragoe et al, J. Med. Chem., (1982) 25, 567-579 and the other, "Agents for the Treatment of Brain Edema" 2. "[(2,3,9,9a-tetrahydro-3-oxo-9a-subtituted-1H-fluoren-7-yl)oxy]alkanoic Acids and Their Analogs", by Cragoe et al, Med. Chem., 29, 825-841 (1986), report recent experimental testing of agents for treatment of brain injury and review the current status of treatment of brain injury. Additionally, U.S. Pat. Nos. 4,316,043, 4,317,922, 4,337,354, 4,356,313, 4,356,314, 4,389,417, 4,394,385, 4,463,208, 4,465,850, 4,579,869, and 4,604,396 disclose certain alkanoic acids, cycloalkanoic acids or their amidine analogs for the treatment of grey matter edema.
The compounds of the invention have the added advantage of being devoid of the pharmacodynamic, toxic or various side effects characteristic of the diuretics, steroids and barbiturates. ##STR1## wherein: R is ##STR2## R' is lower alkyl, branched or unbranched, containing from 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, isopropyl and the like, aryl such as phenyl, halo substituted aryl such as p-fluorophenyl, o-fluorophenyl, p-chlorophenyl and the like, aralkyl such as benzyl, cycloalkyl containing from 3 to 6 nuclear carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and the like, or cycloalkyl-lower alkyl containing from 4 to 7 total carbon atoms such as cyclopentylmethyl and the like;
R" is=O, or H plus ##STR3## R.sup.1 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 carboxyalkyl such as 1-carboxy-1-methylethyl; PA1 R.sup.2 is NH.sub.2, NHR.sup.4 or NR.sup.4 R.sup.5 ; PA1 R.sup.3 is NH or NR.sup.4 ; PA1 R.sup.4, R.sup.5 are each independently lower alkyl, branched or unbranched, containing from 1 to 5 carbon atoms, or amino, provided that R.sup.4 and R.sup.5 are not both amino; PA1 R" is =O, H plus ##STR8##
wherein R.sup.2 and R.sup.3 may be joined together via R.sup.4 to form a heterocyclic ring of 5 or 6 atoms containing 2 nitrogen atoms and 3 or 4 carbon atoms, such as: ##STR4## or wherein R.sup.4 and R.sup.5 may be joined together to form a 5- or 6-membered ring containing one nitrogen atom and 4 or 5 carbon atoms, such as: ##STR5## X and Y are halo or lower alkyl, such as methyl; and x is 1 to 4.
When R" is .dbd.O, the 9a-carbon atom in the molecule is asymmetric, the compounds of the invention are racemic. However, these compounds or their precursors can be resolved so that the pure enantiomers can be prepared, thus the invention includes the pure enantiomers. This is an important point since some of the racemates consist of one enantiomer which is much more active than the other one. Furthermore, the less active enantiomer generally possesses the same intrinsic toxicity as the more active enantiomer. In addition, it can be demonstrated that the less active enantiomer depresses the inhibitory action of the active enantiomer at the tissue level. Thus, for three reasons it is advantageous to use the pure, more active enantiomer rather than the racemate.
When R" is other than .dbd.O, both the 9 and the 9a-carbon atoms are asymmetric, thus these compounds consist of two diasteriomers which can be separated by physical methods. Then, each diasteriomer which are racemic can be separated by classic resolution methods to the component enantiomers. This invention includes pure diasteriomers, the racemates and the pure enantiomers.
Since the alkanimidamide products of the invention are basic, the invention also includes the obvious pharmaceutically acceptable acid addition salts such as the hydrochloride, hydrobromide, sulfate, isethionate, acetate, methanesulfonate, maleate, succinate and the like salts.
Likewise, since the alkanoic acid products of the invention are acidic, the invention also includes the obvious pharmaceutically acceptable salts such as the sodium, potassium, ammonium, trimethylammonium, piperazinium, 1-methylpiperazinium, guanidinium, bis-(2-hydroxyethyl)ammonium, N-methylglucosammonium and the like salts.
It is also to be noted that the compounds of Formula I, as well as their salts, often form solvates with the solvents in which they are prepared or from which they are recrystallized. These solvates may be used per se or they may be desolvated by heating (e.g. at 70.degree. C.) in vacuo.
Although the invention primarily involves novel [(5,6-dichloro-3-oxo-9,9a-disubstituted-2,3,9,9a-tetrahydrofluoren-7-yl)ox y]alkanoic acids and alkanimidamides, and their salts, it also includes their derivatives, such as the esters, amides, oximes, hydrazones and the like. Additionally, this invention includes pharmaceutical compositions in unit dosage form containing a pharmaceutical carrier and an effective amount of a compound of Formula I, its R or S enantiomer, or the pharmaceutically acceptable salts thereof, for treating brain injury. The method of treating a person with brain injury by administering said compounds or said pharmaceutical compositions is also a part of this invention.